Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/465—Nicotine; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/14—Decongestants or antiallergics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
  • A61K9/122—Foams; Dry foams
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to a bioerodible patch comprising a pharmaceutically active agent.
• the composition is designed to adhere to surfaces of mammals, and in particular to dermal and/or mucosal surfaces of mammals, and enables localized delivery of a pharmaceutically active agent to particular target site.
• Bioadhesive carriers are known in the art and include gels, pastes, tablets and films. Commonly, mucoadhesive devices are in the form of a film or a patch which are designed to adhere upon application to a mucus membrane.
• U.S. Pat. No. 5,800,832 discloses a water-soluble, bioerodible pharmaceutical delivery device for application to mucosal surfaces.
• the device comprises an adhesive layer and a non-adhesive backing layer.
• the delivery device of U.S. Pat. No. 5,800,832 has the disadvantage that the pharmaceutically active agent may be incompatible with the ingredients of the layers, which may result in precipitation of the active agent. In such a case the active agent cannot be uniformly distributed within the layers of the composition. Such incompatibilities can prevent entire classes of active agents being incorporated within the mucoadhesive device.
• US 2003/0194420 A1 discloses a bioerodible, water-soluble carrier device comprising a non-bioadhesive backing layer, a bioadhesive layer and a composition comprising an active ingredient, wherein the composition is deposited onto a surface of either the non-bioadhesive backing layer or the bioadhesive layer after formation of the bioerodible, water-soluble, carrier device.
• US 2003/0194420 A1 describes a process of preparing a mucoadhesive device which relies on depositing the active agent onto the surface of the device.
• One of the disadvantages of US 2003/0194420 A1 is that the active agent will not be uniformly distributed in the active-containing layer of the device and as a result will not allow controlled release.
• a bioerodible patch comprising at least one bioadhesive layer and at least one non-bioadhesive layer, wherein the bioadhesive layer comprises at least one polyaphron dispersion and at least one bioadhesive polymer, and wherein the polyaphron dispersion comprises at least one pharmaceutically active agent.
• the use of the patch for treating illness, infections or diseases.
• the patch as described herein for treating depression, diabetes, drug addiction, epilepsy, fungal infection, gout, hypertension, malaria, migraines, Parkinson's disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, psoriasis, water retention or gastro-intestinal infection.
• the patch as described herein for the manufacture of a medicament for treating depression, diabetes, drug addiction, epilepsy, fungal infection, gout, hypertension, malaria, migraines, Parkinson's disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, psoriasis, water retention or gastro-intestinal infection.
• a method of making the patch as described herein comprising forming a polyaphron dispersion comprising a pharmaceutically active agent; mixing said polyaphron dispersion and a bioadhesive polymer to form the bioadhesive layer and providing on said bioadhesive layer a non-bioadhesive layer.
• a method of making the patch as described herein comprising forming a non-bioadhesive layer; and providing on said non-bioadhesive layer a bioadhesive layer, wherein the bioadhesive layer comprises a polyaphron dispersion comprising a pharmaceutically active agent and a bioadhesive polymer.
• polyaphron dispersion as used herein is meant a particular kind of hydrophilic liquid-in-hydrophobic liquid or hydrophobic liquid-in-hydrophilic liquid dispersion comprising (a) a hydrophilic liquid miscible phase, (b) a second hydrophobic phase being immiscible or substantially immiscible with the first phase and (c) one or more surfactants, wherein the dispersed or discontinuous phase is in the form of small (e.g. micron to sub-micron diameter, but more usually at least 1 micron diameter) droplets, and the whole having the following characteristics, which distinguish polyaphron dispersions from conventional or common emulsions and other dispersion types:
• Polyaphron dispersions are sometimes referred to as ‘Biliquid Foams’, ‘High Internal Phase Emulsions (HIPEs)’, ‘High Internal Phase Ratio Emulsions (HIPREs)’ and ‘Gel Emulsions’. All such descriptions that refer to dispersions having the characteristics described above are polyaphron dispersions as used in the present invention.
• the bioerodible patch of the present invention may be used in the localized treatment of body tissues, diseases, or wounds. It may be applied to the skin to allow transdermal delivery of the active agent.
• the patch may be of particular use when applied to moist surfaces of mammals that are susceptible to bodily fluids, such as the mouth, or other types of mucosal surfaces.
• Mucosal surfaces include, but are not limited to corneal, conjunctival, nasal, buccal, sublingual, pulmonary, stomachic, intestinal, uteral, bladder, rectal and vaginal surfaces.
• the pharmaceutically active agent is delivered to the target site, the surrounding tissues, and other bodily fluids.
• the device preferably provides an appropriate residence time for effective drug delivery at the application site.
• bioadhesive layer comprising a bioadhesive polymer and a polyaphron dispersion, wherein the polyaphron dispersion comprises at least one pharmaceutically active agent.
• the polymer comprising the polyaphron dispersion may be formed into a single homogenous mass capable of being moulded into a desired shape.
• Such bioadhesive layers provide for the controlled release of the pharmaceutically active agent(s) over a specified period of time as the polymer dissolves and/or disintegrates.
• the polyaphron dispersion may be distributed throughout, and preferably distributed evenly throughout the bioadhesive layer, a substantially constant release profile of the pharmaceutically active agent may be achieved.
• the pharmaceutically active agent may be uniformly distributed throughout the bioadhesive layer in a solvated form. This is particularly advantageous for oil-soluble active agents, in which case the active agent may be dissolved in the oil phase of the polyaphron dispersion.
• bioerodible patch of the present invention is that when the patch is in position, in for example the buccal cavity, the presence of the non-bioadhesive layer helps to direct the release of the pharmaceutically active agent through the mucosa. This reduces the inefficient loss of the active agent into the mouth, and therefore improves the efficiency of the drug delivery.
• the pharmaceutically active agent may be present in a solvated form in the polyaphron dispersion good permeation into the mucosal membrane or skin or other bodily surface is achieved.
• the bioerodible patch of the present invention allows the delivery of a pharmaceutically active agent at a high concentration, at a specific location in an appropriate form to enable efficient uptake by the human/animal.
• the pharmaceutically active agent may be dissolved in a suitable solvent it is possible to provide a patch comprising the pharmaceutically active agent at an appropriate concentration (for the specific use for which the patch is designed) for enhanced delivery to, for example, the mucous membrane.
• a further advantage of the present invention is provided by the properties of polyaphron dispersions.
• the polyaphron dispersion is comprised within the bioerodible patch.
• the bioerodible patch dissolves and/or disperses polyaphron dispersion droplets are released, and remain as individual droplets.
• the released polyaphron droplets are therefore capable of existing as discrete and separate entities with minimal risk of coalescence to produce larger droplets.
• the discrete droplets maintain their high surface area through which the pharmaceutically active agent molecules may diffuse into or through the mucous membrane for local or systemic uptake. This is in contrast to, for example, emulsions wherein if an emulsion is entrapped within a polymer matrix, when the polymer matrix dissolves the emulsion tend to coalesce.
• a further advantage of the present invention is that more than one polyaphron dispersion may be present in the patch.
• Each polypahon dispersion may comprise one or more pharmaceutically active agents, which may be present in the continuous or discontinous phase. This allows a patch to be provided which may encompass pharmaceutically active agents which are incompatible with one another using traditional delivery methods to be delivered to a target site in the same patch without detrimental stability issues.
• bioerodible patch as used herein means that when the patch is in use in place on a human/animal surface, the components of the patch disperse and/or dissolve under the prevailing conditions such that the polyaphron dispersion, and hence the pharmaceutically active agent is released from the patch. This allows the patch to dissolve/disintegrate over a period of time, with natural body fluids slowly dissolving and eroding the away the patch. Additionally, or alternatively physical abrasion of the patch in place on a human/animal surface may aid the dispersion and/or dissolution of the patch. Unlike bandages, transdermal devices and other non-water soluble film systems, the user does not have to remove the patch following treatment.
• the patch is designed such that when it is placed in contact with water, or an aqueous environment (such as saliva, gastric juices, or plasma from open wounds) the patch disintegrates and/or dissolves, releasing the polyaphron dispersion and the pharmaceutically active agent.
• an aqueous environment such as saliva, gastric juices, or plasma from open wounds
• Suitable polymers for use in the present invention may be water-dispersible and/or a water-soluble. Alternatively, or in addition, the polymer might undergo acid dissolution.
• the decomposition of the bioerodible patch may be a result of interaction of acidic/basic conditions and/or enzyme action with the polymers making up the patch.
• Suitable periods of time for disintegration/dissolution will depend on the intended use of the patch.
• the patch is designed for oral use, typically at least 50%, more preferably at least 60%, more preferably still at least 80% of the bioadhesive layer will disintegrate and/or dissolve within 20 minutes, more preferably within 10 minutes, more preferably still within 7 minutes of being in placed in the sublingual cavity.
• the rate of disintegration and/or dissolution of the bioadhesive layer will be much slower.
• the disintegration and/or dissolution of the bioadhesive layer may take from minutes to hours or days, depending on the choice of components.
• the bioadhesive layer comprises a bioadhesive polymer.
• bioadhesive polymer refers to a polymer which adheres to a biological surface, such as a mucous membrane or skin tissue, preferably for an extended period of time.
• Bioadhesive polymers are known in the art, for example in U.S. Pat. No. 5,474,768.
• Example 2 of U.S. Pat. No. 5,474,768 discloses a procedure for measuring the force required to separate two layers of freshly exercised rabbit stomach tissue that are adhered together by a bioadhesive polymer.
• a bioadhesive polymer can be defined as a material that requires a force of at least about 50 dynes/cm 2 to separate two adhered, freshly excised pieces of rabbit stomach tissue.
• the non-bioadhesive layer is designed so that it will not significantly adhere to such surfaces.
• the bioadhesive layer will adhere to the mucosal tissue in the sublingual area and will avoid detachment in normal use until the bioerosion (and drug delivery) has occurred.
• the non-bioadhesive layer will be sufficiently non-bioadhesive that it does not stick to the tongue, and will hence avoid competitive adhesion which may result in detachment of the patch.
• Suitable bioadhesive polymers include polyacrylic acid, modified polyacrylic acid, sodium carboxymethyl cellulose, carboxymethyl cellulose, hydroxyethylcellulose, polyvinvylpyrrolidone, cetylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, hydroxyethylmethyl cellulose, methylcellulose, hyaluronic acid, polysaccharides, pectin, chitosan, pullulan, tragacanth, sodium hyaluronate, gum arabica, modified starches, and Gantrez polymers (copolymers of methyl vinyl ether and maleic anhydride) and mixtures thereof.
• the bioadhesive layer comprises polyvinyl alcohol. These polymers may be crosslinked. It will be understood that other bioadhesive polymers may be used in the present invention if they have suitable mucoadhesive and/or dermal adhesive properties.
• the degree of bioadhesion will improve with molecular weight and with functionality (and in the case of polyvinyl alcohol with the degree of hydrolysis).
• One skilled in the art will know the grades of polymer to use for the purpose of bioadhesion.
• the form of the polymer may influence the bioadhesion of the patch. If the polymer is partially hydrated prior to application at the point of use, typically the bioadhesion will be worse than if the polymer is dehydrated and then subsequently hydrated by the environment at the point of use. Subsequent hydration of the polymer may occur as a result of, for example, the interaction with the mucous membrane, saliva and/or blood.
• the bioadhesive layer preferably comprises from 1 to 99% by weight of bioadhesive polymer, more preferably from 10 to 70% by weight, more preferably still from 40 to 60% by total weight of the bioadhesive layer.
• the bioadhesive layer and/or the non-bioadhesive layer of the present invention may comprise a film forming polymer.
• Suitable film forming polymers are well known in the art and include, but are not limited to, cellulose acetate, cellulose acetate butyrate, polyvinylpyrrolidone, polyvinyl alcohol, maltodextrin, pullulan, modified starches, polyacrylic acid (high molecular weight), starch acetate, polyvinylpyrrolidone/polyvinylacetate copolymer, xantham gum, copolymers of lactic acid, caprolactone and glycolic acid and mixtures thereof.
• Cross-linked or plasticized film-forming polymers may be used to alter the dissolution kinetics of the layers.
• the non-bioadhesive layer preferably comprises from 0 to 99% by weight of film forming polymer, more preferably from 0 to 30% by weight, more preferably still from 0 to 10% by total weight of the non-bioadhesive layer.
• suitable polymers for use in the bioadhesive and/or non-bioadhesive layers are capable of undergoing a sol-gel transition by reason of temperature change (for example, gelatine) or by reason of crosslinking (for example the crosslinking of alginate salts by calcium ions) and include, for example, gelatine, pectins, agar agar, carrageens, alginates, other water dispersible or water soluble mouldable polymers known in the art. Mixtures of the above may also be used in the present invention.
• Preferred polymers include gelatine and carageenan gum. Most preferably, the polymer is gelatine.
• Dried polymer powder may also be used in order to form the patch or to form part of the patch.
• suitable polymers in powder form include, but are not limited to, modified polyacrylic acid (for example, Noveon AA-1, Carbopol 974), gantrez polymers and carboxymethyl cellulose.
• Plasticizers may be selected from, for example, the group consisting of polyalcohol organic acids, hydroxyl acids, amines, acid amines, sulphoxides and pyrrolidones.
• the plasticizer is selected from the group of sorbitol, mannitol, glycerol, xylitol, maltitol (Maltisorb®), propylene glycol, polyethylene glycol, lactitol, trehalose, sorbitan esters and sorbitol anhydride and mixtures thereof.
• the bioadhesive layer preferably comprises from 0 to 30% by weight of a plasticizer, more preferably from 5 to 20% by weight, more preferably still from 10 to 15% by weight, all percentages being based on the total weight of the bioadhesive layer.
• the non-bioadhesive layer preferably comprises from 0 to 35% by weight of a plasticizer, more preferably from 5 to 20% by weight, more preferably still from 10 to 15% by weight, all percentages being based on the total weight of the non-bioadhesive layer.
• the consistency of the layers of the patch may be varied from a gel-like consistency to a solid consistency by careful choice of ingredients.
• the amount and choice of the plasticizer will help to determine the hardness of the final product. It may also effect the disintegration and/or dissolution of the moulded body, as well as its physical and chemical stability.
• the polymers used in the layers of the present invention may be chosen such that they are sensitive to acidity or alkalinity so that the release of the entrapped pharmaceutically active agent(s) may be determined by a change of pH or by the presence of another chemical species.
• the bioerodible patch of the present invention preferably comprises from 1 to 95% by weight of bioadhesive layer, more preferably from 10 to 40% by weight, more preferably still from 15 to 25% by weight of the total bioerodible patch.
• the bioerodible patch of the present invention preferably comprises from 5 to 99% by weight of non-bioadhesive layer, more preferably from 60 to 90% by weight, more preferably still from 75 to 85% by weight of the total bioerodible patch.
• the amount of polyaphron dispersion in the bioadhesive layer may be as high as 60% by weight of the total bioadhesive layer.
• the amount of polyaphron dispersion in the bioadhesive layer is at least 20%, more preferably at least 30%, more preferably still at least 40% by weight of the total bioadhesive layer.
• the discontinuous phase of the polyaphron dispersion comprises a pharmaceutically acceptable oil phase.
• oils which may be used in the discontinuous phase of the aphrons include almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grapeseed oil, mustard seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, squalene, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, modified triglycerides, caprylic/capric glycerides, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl
• Examples of mono and diglycerides which may be used in the present invention include propylene glycol mono and diesters having from 15 to 40 carbon atoms, including hydrolysed coconut oils (e.g. Capmul MCM), hydrolysed corn oil (e.g. Maisine 35-1).
• hydrolysed coconut oils e.g. Capmul MCM
• hydrolysed corn oil e.g. Maisine 35-1).
• the monoglycerides and diglycerides are mono- or di-saturated fatty acid esters of glycerol having eight to sixteen carbon chain length.
• Essential oils may also be used in the present invention.
• a suitable antioxidant may be added to the oil.
• the bioadhesive layer comprises from 1 to 60% by weight of pharmaceutically acceptable oil, more preferably from 10 to 50% by weight, more preferably still from 20 to 40% by weight based on the total weight of the bioadhesive layer.
• the continuous hydrophilic phase of the polyaphron dispersion comprises water.
• the continuous hydrophilic phase may additionally comprise a co-solvent such as an aliphatic alcohol, polyethylene glycol, propylene glycol or glycerol, or mixtures thereof, and/or a gelling agent, thickening agent, rheology modifier and a stabiliser.
• Suitable gelling agents include alginate gums or their salts, guar gum, locust bean gum, xanthan gum, gum acacia, gelatin, hydroxymethyl-cellulose hydroxyethylcellulose, hydroxypropyl-cellulose, carboxymethylcellulose or its salts, bentonites, magnesium aluminium silicates, “Carbomers” (salts of cross-linked polymers of acrylic acid), or glyceryl polymethacrylates or their dispersions in glycols, or a polyvinylpyrrolidone polymer or a water-dispersible copolymer thereof, or any appropriate mixture of any of these polymers and gums.
• the hydrophilic phase may be non-aqueous, or essentially non-aqueous.
• the hydrophilic phase may be, for example, an aliphatic alcohol, polyethylene glycol, propylene glycol or glycerol, or mixtures thereof.
• the surfactants used in the present invention may be incorporated into either or both phases of the polyaphron dispersion(s).
• the surfactant used in the present invention is preferably an alkyl polyglycol ether, an alkyl polyglycol ester, an ethoxylated alcohol, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, an ionic or non-ionic surfactant, a hydrogenated castor oil/polyoxyethylene glycol adducts containing from 25 to 60 ethoxy groups a castor oil/polyoxyethylene glycol adduct containing from 25 to 45 ethoxy groups, a sorbitan fatty acid ester (for example Span 20 or Span 80), a block copolymer of ethylene oxide and propylene oxide (for example Pluronic L121 or Pluronic F68), or a mixture thereof.
• the bioerodible patch of the present invention comprise less than 5% by weight of surfactant, more preferably less than 2% by weight, more preferably still less than 1% by weight of the bioerodible patch.
• the pharmaceutically active agent may be substantially present in either the continuous or the discontinuous phase of the polyaphron dispersion. Alternatively, the pharmaceutically active agent may be substantially present in both the continuous and the discontinuous phase. This will in part be determined by the solubility of the pharmaceutically active agent in a specific phase.
• the bioadhesive layer comprises from 0.0001 to 60% by weight of pharmaceutically active agent, more preferably from 0.1 to 50% by weight, more preferably still from 1 to 30% by weight based on the total weight of the bioerodible patch.
• pharmaceutically active agent will depend on a number of factors. For example, it will depend on the proposed method of application of the patch, i.e. dermal or sublingual, on the specific pharmaceutically active agent used, the solubility of the active agent and the purpose of the treatment.
• the pharmaceutically active agent is a “poorly water soluble drug”, preferably it is dissolved in the oil phase of the polyaphron dispersion.
• poorly water soluble is meant a drug which will dissolve in water in an amount of less than 1% by weight.
• a suitable co-emulsifier is a phosphoglyceride, a phospholipid, for example lecithin, or a free fatty acid that is liquid at room temperature, for example iso-stearic acid, oleic acid, linoleic acid or linolenic acid.
• the pharmaceutically active agent may, for example, be selected from an analgesic or anti-inflammatory agent, an anthelmintic, an anti-arrhythmic agent, an anti-coagulant, an anti-depressant, an anti-diabetic agent, an anti-epileptic agent, an anti-fungal agent, an anti-gout agent, an anti-hypertension agent, an anti-malarial, an anti-migraine agent, an anti-muscarinic agent, an anti-neoplastic agent, an anti-protozoal agent, an anti-thyroid agent, an anxiolytic, sedative, hypnotic or neuroleptic agent, a corticosteroid, a diuretic, an anti-Parkinsonian agent, a gastro-intestinal agent, a histamine H1-receptor antagonist, a lipid regulating agent, an anti-anginal agent, a thyroid agent, a nutritional agent, an antipyretic agent, an antibacterial agent, an immunosuppressant, an antiviral
• the stimulant is nicotine.
• Examples of pharmaceutically active agents which may be used in the present invention include the following:
• Analgesics and anti-inflammatory agents aceclofenac, aloxiprin, auranofin, azapropazone, buprenorphine, benorylate, capsaicin, celecoxib, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, ibuproxam, indomethacin, ketoprofen, lornoxicam, meclofamate, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, oxyphenbutazone, phenylbutazone, piroxicam, refocoxib, sulindac, suxibuzone, tolmetin, zileuton.
• Anthelmintics albendazole, bephenium hydroxynaphthoate, dichlorophen, ivermectin, mebendazole, oxfendazole, oxantel, praziquantel, pyrantel, thiabendazole.
• Anti-arrhythmic agents amiodarone, disopyramide, quinidine sulphate.
• Anti-bacterial agents benethamine penicillin, cinoxacin, ciprofloxacin, clarithromycin, clofazimine, cloxacillin, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim, cefrozil, fusidic acid, muciprocin, nifuroxazide, oxacillin, sparfloxacin, sulphadoxin, telithromycin, trovafloxacin.
• Anti-coagulants dicoumarol, dipyridamole, nicoumalone, phenindione, clopidogrel, tirofibran.
• Anti-depressants amoxapine, maprotiline, trimipramine, paroxetine, sertraline.
• Anti-diabetics acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, insulin, tolbutamide, rasiglitazone, pioglitazone, andglimepiride.
• Anti-epileptics beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide, methylphenobarbitone, phenacemide, phenobarbitone, phenyloin, phensuximide, primidone, sulthiame, valproic acid, and tiagabine.
• Anti-fungal agents azithromycin, oxiconazole, tolnaftate, voriconazole, amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, sulconazole nitrate, terbinafine, terconazole, tioconazole, undecenoic acid.
• Anti-gout agents allopurinol, probenecid, sulphin-pyrazone.
• Anti-hypertensive agents amlodipine, benidipine, candesartan cilexitil, clonidine, darodipine, diazoxide, eprosartan, felodipine, irbesartan, irinotecan, isradipine, losartan, minoxidil, nicardipine, nifedipine, nimodipine, prazosin, raubasine, reserpine, tamsulosin, telmisartan, valsartan.
• Anti-malarials amodiaquine, chloroquine, halofantrine, mefloquine, proguanil, pyrimethamine, quinine sulphate.
• Anti-migraine agents dihydroergotamine mesylate, ergotamine, methysergide, pizotifen, alpiropride, eletriptan, frovatriptan, lisuride, naratriptan, rizatriptan, sumatriptan, zolmitriptan.
• Anti-muscarinic agents atropine, benzhexyl, biperiden, hyoscyamine, mepenzolate bromide, tropicamide.
• Anti-neoplastic agents and immunosuppressants aminoglutethimide, amsacrine, anastrazole, azathioprine, bicalutamide, busulphan, chlorambucil, clobetasol, cyclosporine, dacarbazine, estramustine, etoposide, exemestane, gefitinib, letrozole, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, mycophenolate mofetil, nilutanide, paclitaxel, procarbazine, sirolimus, tacrolimus, tamoxifen, testolactone, toremifine.
• Anti-protazoal agents clioquinol, diiodohydroxyquinoline, diloxanide, dinitolmide, furzolidone, metronidazole, nitrofurazone, tinidazole, atovaquone, ornidazole.
• Anti-thyroid agents carbimazole, propylthiouracil.
• Anti-viral agents adefovir dipovoxil, amprenavir, efavirenz, lopinavir, nelfinavir, penciclovir, ritonavir, saquinavir, tipranavir.
• Anxiolytic, sedatives, hypnotics and neuroleptics aripiprazole, eszopaclone, paroxetine, sertindole, zaleplon, zolpidem, alprazolam, amylobarbitone, barbitone, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, clobazam, clozapine, diazepam, droperidol, ethinamate, fluanisone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitraz
• ⁇ -Blockers nadolol, pindolol.
• Bronchodilators and anti-asthma agents Bronchodilators and anti-asthma agents: zafirlukast, zileuton.
• Cardiac Inotropic agents digitoxin, digoxin, lanatoside C, medigoxin.
• Corticosteroids beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, clobetasol, clobetasone, desonide, mometasone, rimexocone.
• Diuretics acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene.
• Anti-parkinsonian agents bromocriptine, apomorphine selegiline.
• Erectile dysfunction agents sildenafil, vardenifil, tadalafil.
• Gastro-intestinal agents bisacodyl, cimetidine, diphenoxylate, domperidone, famotidine, loperamide, droperidol, dronabinol, nabilone, palonosetron, granisetron, ondansetron, pizotifen, mesalazine, omeprazole, sulphasalazine.
• Antihistamines cinnarizine, cyclizine, cyproheptadine, dimenhydrinate, meclozine, oxatomide, terfenadine, acrivastine, antazoline, azatadine, azelastine, bramazine (bromodiphenhydramine), brompheniramine, buclizine, carbinoxamine, cabastin, carebastine, cetirizine, chlorcyclizine, chlorphenamine (chlorpheniramine), chlorphenoxamine, chloropyrilene, cinnarizine, clemastine, clocinizine, cyclizine, cyproheptadine, deptropine, desloratidine, diphenylhydramine, dimenhydrinate, diphenylpyraline, doxylamine, ebastine, embramine, emedastine, epinastine, fexofenadine, flunariz
• Lipid regulating agents bezafibrate, clofibrate, lovastatin, pravastatin, rosuvastatin, simvastin, fenofibrate, gemfibrozil, probucol.
• Nitrates and other anti-anginal, agents amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, pentaerythritol tetranitrate.
• Nutritional agents betacarotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K, vitamin B12.
• Opioid analgesics codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol, morphine, pentazocine, fentanyl.
• Sex hormones clomiphene, danazol, ethinyl estradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, conjugated oestrogens, progesterone, stanozolol, stibestrol, testosterone, tibolone.
• Stimulants dexamphetamine, dexfenfluramine, mazindol, nicotine.
• the viral vector may be a retrovirus (such as Moloney murine leukaemia virus), a lentivirus, an adenovirus, an adeno-associated virus (AAV) or a nanoengineered substance such as Ormosil.
• retrovirus such as Moloney murine leukaemia virus
• lentivirus such as Moloney murine leukaemia virus
• adenovirus such as adenovirus
• AAV adeno-associated virus
• nanoengineered substance such as Ormosil.
• the active agent may be a monoclonal antibody.
• Suitable salts, isomers and derivatives thereof may be substituted for these drugs.
• Suitable pharmaceutical salts include, for example, hydrochloride, maleate, tartrate, embonate. Mixtures of pharmaceutically active agents may be used where therapeutically effective.
• the bioerodible patch of the present invention is preferably presented in a unit dosage form.
• Each patch dosage may comprise from 0.05 mg to 500 mg, and in particular from 0.1 mg to 20 mg of the pharmaceutically active agent. It will be understood that the preferred unit dosage will depend on the particular pharmaceutically active agent used and the intended method of application of the patch.
• flavouring agents may also be added. Any suitable amount and type of artificial and/or natural flavouring agents can be used in any sensorially acceptable fashion.
• the flavour can constitute 0.1% to 20% by weight of the total weight of the patch, preferably 0.5% to 5% by weight.
• the flavouring agents can include, for example, essential oils, synthetic flavours or mixtures, including but not limited to, oils delivered from plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oils, oil of wintergreen, anise and the like, flavour components with germ killing properties such as menthol, eucalyptol, thymol, and combinations thereof.
• Colouring agents may be included in the patch. These may include, for example, natural food colors and dyes suitable for drug applications, and may be present in amounts from 0.01% to 1.5% by weight of the total patch.
• the non-bioadhesive layer comprises a flavouring agent and/or a colouring agent.
• the non-bioadhesive layer comprises at least one polyaphron dispersion.
• the polyaphron dispersion may comprise a flavouring agent, a colouring agent, a taste-masking composition and/or a fragrance or odour neutralising/masking component.
• the patch of the present invention may comprise an opacifer, or a mixture of opacifers.
• the opacifer may be added in order to obtain an opaque patch or in order to protect light sensitive pharmaceutically active agents dispersed within said patch.
• Opacifers may be present in an amount of from 0.01% to 5% by weight, preferably 0.1% to 3% by weight of the total weight of the patch and may be selected from the group of titanium dioxide, calacium carbonate, iron oxide and bentonite clay and talc.
• the opacifer is titanium dioxide.
• the patch may comprise disintegrants, fillers and bulking materials. Salt and other low molecular weight highly soluble materials may also be included to aid dissolution. In addition and/or alternatively, the presence of salts may influence the osmotic process and stabilisation of the patch.
• the presence of bulking materials and fillers in the patch may be useful in aiding the processing and manufacture of the patch (for example speeding up drying). Furthermore, they may assist the final dissolution and the performance of the patch.
• the patch may comprise from 0.1 to 40% by weight of bulking materials and/or fillers based on the total dry weight of the patch, preferably from 5 to 30% and more preferably from 15 to 25% by weight.
• Suitable bulking materials and fillers are calcium carbonate, pigments, fumed silicas, microcrystalline cellulose, calcium phosphate, magnesium aluminium silicate and bentonite and kaolin clays.
• the pharmaceutically active agent is nicotine
• the non-bioadhesive layer comprises a flavouring agent
• the bioerodible patch is a sublingual patch, comprising a bioadhesive layer and a non-bioadhesive layer, wherein the bioadhesive layer comprises a polyaphron dispersion and a bioadhesive polymer, and wherein the polyaphron dispersion comprises a pharmaceutically active agent.
• the pharmaceutically active agent is nicotine.
• the non-bioadhesive polymer comprises gelatine, and a flavouring agent.
• the bioadhesive layer comprises polyvinyl alcohol and/or polyvinylpyrrolidone.
• the bioadhesive layer adheres to the floor of the sublingual cavity such that the non-bioadhesive may contact the underside of the tongue of the user.
• This embodiment has several advantages.
• the formulation of this embodiment provides a strong, flexible and comfortable patch.
• the flavouring agent present in the non-bioadhesive layer provides a taste masking function. This may be of particular use when the pharmaceutically active agent has an unpleasant taste, for example, nicotine.
• the bioerodible patch may be designed such that either the bioadhesive or the non-bioadhesive layer dissolves and/or disperses at a faster rate that the other layer.
• the patch is a sublingual patch
• the non-bioadhesive layer comprises a tasking masking or flavouring agent
• for the non-bioadhesive layer to dissolve and/or disperse at a slower rate than the bioadhesive layer.
• the bioerodible patch may comprise more than one bioadhesive and/or non-bioadhesive layers.
• the size and shape of the bioerodible patch will be determined by the desired use of said patch, for example, for dissolving in the mouth, or for applying to an open wound or inserting into the rectum or vagina as required. Suitable shapes include disks, ellipses, squares, rectangles and parallepipedes.
• the surface area of the non-bioadhesive layer is preferably larger than the surface area of the bioadhesive layer.
• the thickness of the device may vary, depending on the thickness of each of the layers.
• the bilayer thickness ranges from 0.05 to 3 mm, and more preferably from 0.2 to 2 mm and even most preferably between 0.3 and 1.5.
• the thickness of each layer may vary from 10 to 99% of the overall thickness of the device, and preferably varies form 30 to 60%.
• the bioerodible patch as described herein may further comprise at least one peelable sheet which may be provided on either or both the bioadhesive layer and/or the non-bioadhesive layer.
• a peelable sheet is provided at least on the bioadhesive layer.
• Suitable materials for said peelable sheet will be well known in the art and include, but are not limited to, for example, polyethylene, polyethleneterephthalate, polypropylene, polystyrene, polyvinylchloride, and polyvinyl acetate.
• the bioerodible patch of the present invention may be provided in an airtight packaging system in order to prevent deterioration. Suitable systems are known in the art.
• bioerodible patch for use in buccal or sublingual delivery is that, unlike absorption from the gut, the pharmaceutically active agent enters the systematic circulation from the buccal cavity at a point where the blood does not immediately go through the liver (where much of it is metabolised before it can perform its desired effect). Avoidance of heptatic metabolism dramatically improves the bioavailablity of the pharmaceutically active agent.
• the patch of the present invention has the advantage that the bioadhesive and non-bioadhesive layers may be formulated to be soft, pliable and comfortable to use whilst having a relatively high concentration of pharmaceutically active agent, and in particular oil-soluble pharmaceutically active agent, for release in a readily absorbed form.
• pharmaceutically active agent and in particular oil-soluble pharmaceutically active agent
• Many of the buccal delivery dosage forms known in the art are not suitable for delivering poorly water soluble drugs.
• the patch of the present invention may be held in place by the bioadhesive layer, advantageously the pharmaceutically active agent will generally not be lost by swallowing, thus a more consistent dose is provided.
• the bioerodible patch comprises a bioadhesive layer, wherein the bioadhesive layer comprises a first polyaphron dispersion comprising a first pharmaceutically active agent and a further second polyaphron dispersion comprising a further second pharmaceutically active agent.
• the first and second pharmaceutically active agent may be the same or different.
• the pharmaceutically active agents may be, for example, nadolol and lorazepam (for anxiety), azelastine and ketoprofen (for antihistamine and pain), simvastatin and ezetimbe (statin in combination with a cholesterol absorption inhibitor).
• a wound dressing comprising the bioerodible patch as described herein.
• a bioerodible capsule comprising the bioerodible patch as described herein.
• suitable materials for making a bioerodible capsule include, for example, HPMC (hydroxypropylmethyl cellulose) with an enteric coating such as cellulose acetate phthalate.
• HPMC hydroxypropylmethyl cellulose
• enteric coating such as cellulose acetate phthalate.
• a method of making the patch as defined herein comprising forming a polyaphron dispersion comprising a pharmaceutically active agent; mixing said polyaphron dispersion and a bioadhesive polymer to form the bioadhesive layer and providing on said bioadhesive layer a non-bioadhesive layer.
• the bioadhesive layer may be formed by printing the bioadhesive polymer onto either a temporary surface or onto a pre-existing layer.
• a method of making the bioerodible patch as described herein comprising forming a non-bioadhesive layer; and providing on said non-bioadhesive layer a bioadhesive layer, wherein the bioadhesive layer comprises a polyaphron dispersion comprising a pharmaceutically active agent and a bioadhesive polymer.
• the non-bioadhesive layer may be formed by printing the non-bioadhesive polymer onto either a temporary surface or onto a pre-existing layer.
• the bioadhesive layer when the bioadhesive layer comprises a bioadhesive film forming polymer comprising a polyaphron dispersion, the bioadhesive layer may be formed by casting the film forming polymer and allowing it to dry. When the film is dry the non-bioadhesive layer may be provided on the bioadhesive layer and allowed to dry (if the non-bioadhesive layer comprises a film-forming polymer), or allowed to go through a sol gel transition (if, for example, gelatine is used).
• the layers may be dried, partially dried, or may be wet before application of the second layer.
• the bioadhesive and/or non-bioadhesive layer may be formed by techniques known in the art such as by printing, film dipping, film coating, film casting, spin coating or by spraying followed by drying.
• the coating solution may be applied using a variety of methods including doctor blade, extrusion, roller, spraying, brush painting or wiping.
• the layer may be produced on an appropriate support such as a temporary surface or onto a pre-existing layer.
• the solution may be applied at the desired thickness and dried (if required) using either an oven or preferably a flow of heated gas (such as air).
• the temporary surface may be a polymer-coated paper, Mylar or any other appropriate non-deformable and impervious substrate.
• the surface holds the film dimensionally stable during coating and setting/drying processes but allows the resulting layer/patch to be released (for example by peeling) when required. It may be desirable to cut the film on this substrate to the appropriate desired geometry and then detach the resulting product.
• the solids content of the coating solution, the resulting solution viscosity and coating thickness applied determine the amount of coating film to be deposited on the casting surface.
• appropriate steps may be taken in order to avoid or reduce any degradation or loss of the pharmaceutical agent.
• appropriate steps may include control of temperature, atmosphere, contaminants and light.
• the method of making the patch may require low temperature drying in an inert flowing gas with appropriate filtration and in a darkened environment in order to avoid decomposition or contamination of the pharmaceutical agent.
• Other specific factors may also need to be addressed which would be obvious to one skilled in the art.
• Powdered polymers may be incorporated into the patch either by addition onto another wet (or partially wet) polymer layer or onto a fully dried tacky layer.
• wet the excess water helps to hydrate the polymer causing it to be fixed onto the existing polymer layer.
• the level of water present is not usually enough to fully hydrate/dissolve the powdered polymer, only sufficient to make it adhere.
• the system is subsequently dried further.
• tacky a highly plasticised base layer is cast and dried fully. The powder is then applied in excess to this layer and a certain proportion sticks to the base layer due to that layers inherent tackiness.
• An additional compatibilising (bridging) polymer may be provided between the bioadhesive and the non-bioadhesive layer.
• the additional compatibilising (bridging) polymer binds the bioadhesive and the non-bioadhesive layer together to prevent, or substantially prevent, separation in use.
• a method for administering the bioerodible patch as described herein to a human or animal comprising applying the bioerodible patch as described herein to a mucosal surface of the human or animal.
• Mucosal surfaces include, but are not limited to corneal, conjunctival, nasal, buccal, sublingual, pulmonary, gastric, intestinal, uteral, bladder, rectal and vaginal surfaces.
• This method may be used for the treatment of depression, drug addiction, diabetes, epilepsy, fungal infection, gout, hypertension, malaria, migraines, Parkinson's disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, psoriasis, water retention or gastro-intestinal infection.
• the bioerodible patch may be located locally on a mucousal surface of a patient/mammal for example, by hand or during surgery. Alternatively, or additionally, the bioerodible patch may be located on a mucosal surface of a patient/mammal indirectly, for example, by enclosing the patch of the present invention in a capsule suitable for oral administration.
• a suitable vessel is charged with the aqueous phase of the polyaphron dispersion.
• the oil phase was added at a constant rate with stirring, using a sweep stirrer or an orbital mixer. After completion of the oil addition, the stirring was continued until the size of the oil droplets became stable or reached a desired size.
• Bioadhesive solutions 4 and 5 were heated to 80 degrees centigrade to facilitate the dissolution of the poly(vinylalcohol).
• Bioadhesive layer 4 was exposed to high shear (2000 rpm) mixing to ensure adequate distribution of the pigment particles.
• Bioadhesive layer 6 was made by heating to 55 degrees centigrade with low shear stirring. The system was kept at this temperature until used.
• Bioadhesive layer 1 % (w/w) Weight (g) Polyvinyl alcohol solution 87.3 10 in demin water (20% w/w) Polyaphron dispersion 1 8.4 0.96 Glycerine 4.3 0.50 100 11.46
• Bioadhesive layer 2 % (w/w) Weight (g) Polyvinyl alcohol solution 87.3 10 in demin water (20% w/w) Polyaphron dispersion 2 8.4 0.96 Glycerine 4.3 0.50 100 11.46
• Bioadhesive layer 3 % (w/w) Weight (g) Polyvinyl alcohol solution 91.30 91.30 in demin water (20% w/w) Polyaphron dispersion 3 8.70 8.70 100 100
• Bioadhesive layer 6 Poly (vinyl pyrrolidone) K90 10.0 5.0 Xylitol 5.0 2.5 Gelatine 20.0 10.0 Water 56.00 28.00 Food dye 0.25 0.12 Poly aphron dispersion 6 8.75 4.38 100 50.0 Preparation of Non-bioadhesive Polymer Solutions
• Non-bioadhesive polymer solutions 1 to 5 was dissolved and mixed with low shear stirring at 50 degree centigrade until a homogeneous mixture was produced.
• Non-bioadhesive polymer solution 6 was mixed with low shear stirring at 85 degree centigrade until a homogeneous mixture was produced. All solutions were kept at elevated temperatures until used.
• Non-bioadhesive polymer solution 1 % (w/w) Weight (g) Gelatine GP grade 30 30 Demin water 55 55 Glycerine 15 15 100 100
• Non-bioadhesive polymer solution 2 % (w/w) Weight (g) Polyaphron Dispersion 3 10 1 Non-bioadhesive polymer solution 1 90 9 100 10
• Non-bioadhesive polymer solution 3 % (w/w) Weight (g) Polyaphron Dispersion 4 10 1 Non-bioadhesive polymer solution 1 90 9 100 10
• Non-bioadhesive polymer solution 4 % (w/w) Weight (g) Gelatine 28.24 3.53 Sorbitol 20.00 2.50 Water 51.76 6.47 100.00 12.5
• Non-bioadhesive polymer solution 5 % (w/w) Weight (g) Gelatine 24.53 21.18 Sorbitol 24.53 21.18 Microcrystaline cellulose 5.79 5.00 (Chemfields PH101) Blue food dye 0.17 0.15 Sodium metabisulfite 0.03 0.03 Water 44.95 38.82 100.00 86.36
• Non-bioadhesive solution 6 k-carrageenan 2.0 0.8 Microcrystalline cellulose 15.0 6.0 Xylitol 5.0 2.0 Water 78.0 31.2 100 40.0 Supplementary Layers
• Supplementary Layer 1 % (w/w) Weight (g) Poly(vinylalcohol) (Gohsenol EG-05) 87.76 8.78 solution in Demin water (25.5% wt/wt) Sorbitol 1.73 0.17 Sucrose 10.51 1.05 100.00 10.00 Supplementary Layer 2
• a portion of the bioadhesive 1 was placed in a teflon beaker to form an even thin film which was left to dry under ambient conditions over 2 days to form a dry film (ca 0.3 g)
• a circular disc (ca 1.5 cm diameter) was cut of the dry film generated from drying Bioadhesive layer 1. This had a nicotine total of 2.69 mg calculated.
• the disc was placed on a grooved metal block and coated with a small amount of a polyvinyl alcohol solution (20% w/w) as a binder for the next layer.
• the gelatine solution (non-bioadhesive polymer solution 1) at 50 degree centigrade was drawn over this disc and allowed to cool. When cool the sample was detached from the metal block and placed in a jar to prevent the film drying out.
• the sample was a bioerodible patch with the bioadhesive layer attached to the non bioadhesive layer.
• Example 1 Using the same method as Example 1a dry film was obtained from drying bioadhesive layer 2. A circular disc was cut from the dry film. This had a nicotine total of 1.80 mg calculated. The disc was coated as described in example 1.
• the gelatine sample used was non-bioadhesive polymer solution 2. The sample was a bioerodible patch with the bioadhesive layer attached to the non bioadhesive layer.
• the non-bioadhesive layer 3 is cast on to a polycarbonate sheet using a 1 mm film applicator and allowed to set and air dry. Once dried, Supplementary Layer 1 is applied onto the non-bioadhesive layer. Before the layer is completely dry the supplementary layer 2 is dusted on. The partial solvation of the powder aids the compatibility between the layers.
• bioadhesive layer 3 is applied to a polycarbonate base using a 300 ⁇ m film applicator and dried.
• the oil loading in the dry film is 29.9% w/w. Once dried, circles 1 cm diameter where cut using a borer.
• the small circles of bioadhesive layer were then applied to the powder layer with a small droplet of water to promote adhesion.
• a 1.5 cm diameter circle is then cut using a borer centred on the bioadhesive film to form concentric disks.
• Bioadhesive layer 3 is applied to a polycarbonate base using a 300 ⁇ m film applicator and dried.
• Non-bioadhesive layer 3 is cast using a 700 um film applicator onto a polycarbonate sheet and allowed to set but not dry. Powdered mix of Methocel 40-100 (Dow Chemicals) and Gantrez MS-955 (ISP) in a 80:20 blend is then applied. The powder is left to hydrate from the gelatine layer and dry. A small drop of poly(vinylalcohol) (Gohsenol EG-05) 30% solution is applied to the Methocel/Gantrez layer to act as a bridging layer and the preformed bioadhesive layer then affixed.
• Methocel 40-100 Dens Chemicals
• Gantrez MS-955 ISP
• the bioadhesive layer 5 is applied to a polycarbonate base using a 600 ⁇ m film applicator and dried. Once dried, circles 1 cm diameter where cut using a borer.
• non-bioadhesive layer 5 is cast on to a polycarbonate sheet using a 0.8 mm film applicator and allowed to set and air dry. Once dried, Supplementary. Layer 3 is applied onto the non-bioadhesive layer ( ⁇ 50 ⁇ m). The small circles of bioadhesive layer were then immediately applied followed immediately by Supplementary layer 4 being dusted on in excess and allowed to air dry.
• the non-bioadhesive layer 6 is applied to a polycarbonate base using a 700 ⁇ m film applicator and allowed to cool for 20 minutes.
• a 700 ⁇ m film of bioadhesive layer was then cast on top of the non-bioadhesive layer and allowed to cool. Disks 1.5 cm in diameter were then cut through both layers using cork borer. The bioadhesive layer was then applied to a pre formed poly(vinyl acetate) sheet for ease of storage. The patch could then be peeled off of the backing layer as required for use.

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